Access to highly active anti-retroviral drug therapy has markedly reduced morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). Although the incidence of most of the neurological complications of HIV infection has declined dramatically with the use of these drug regimens, peripheral neuropathy (PN), a devastating complication of nucleoside reverse transcriptase inhibitor (NRTI) therapy, is increasingly common among persons living with HIV/AIDS. The precise mechanisms of nerve damage in PN are unclear, but important factors include: nerve inflammation caused by HIV-infected macrophages, drug-induced mitochondrial abnormalities leading to oxidative stress, and poor nutrition. Iron metabolism is abnormal in HIV infection, but the role of iron, a micronutrient critical for mitochondrial and neuronal function, has not been directly explored in HIV-associated PN. A common variant in the hemochromatosis (HFE) gene, C282Y, causes increased dietary iron absorption and defects in cellular iron transport and immunity. Expression of the HFE-encoded iron-transport protein on macrophages has recently been shown to decrease as result of HIV-1 infection. We previously used clinical data and stored DNA from a large, prospective cohort study conducted by the AIDS Clinical Trials Group (ACTG) to make the seminal observation that HFE C282Y protects against the development of PN during NRTI therapy in HIV/AIDS. Since this iron-loading variant is protective against PN, and iron deficiency is endemic in many populations devastated by HIV/AIDS, it is critical to define the mechanism underlying this protective effect in order to benefit patients globally. The goals of our study are therefore to use cryopreserved serum samples in the same HIV cohort to determine 1) if reduced PN in HFE C282Y carriers is due to increased body iron stores, 2) if time to onset of PN during NRTI therapy is related to iron levels before or soon after starting treatment, 3) if a statistical model incorporating iron stores, early changes in iron levels during NRTI therapy; HFE genotype, and certain high-risk mitochondrial DNA variants can be created to predict the development of PN. Conventional regression as well as newer statistical modeling tools will be used. These studies will generate critical preliminary data for an R01 grant application to fund in-depth mechanistic studies that we hope will ultimately enable clinicians to reduce the incidence of this debilitating complication of HIV/AIDS treatment. [unreadable] [unreadable] [unreadable]